tbuckley/cabot-search huggingface dataset:
Abstract P1033: Derivation Of Large Biorepository Of Human Ipsc Lines For Open Access Sharing Among Academic Investigators
Authors: Christopher D Yan, Celine J Lai, Sushma P Shenoy, Chelsea Lee, Julio V Guevara, Yan Zhuge, Paul D Pang, Joseph C Wu
Journal: Circulation Research (2023)

Background: Human induced pluripotent stem cells (iPSCs) and their ability to differentiate into numerous cell types have revolutionized biomedical and translational research in many fields such as cardiovascular disease, development, aging, regeneration, cancer, personalized medicine, and many rare diseases. The need for obtaining iPSC lines with the associated donors’ clinical data and from patients of diverse genetic backgrounds has been greater than ever. Greenstone Biosciences Inc. (GSB) has built a curated biorepository to address this demand as an asset for the scientific community utilizing iPSCs. Methods: The GSB biobank curates clinical data, isolates peripheral blood mononuclear cells (PBMCs), reprograms and banks patient-specific iPSC lines, and performs quality assurance. Reprogramming of PBMCs to iPSCs is carried out using non-integrating Sendai virus encoding for Oct4, Sox2, Klf4, and c-Myc. We then rigorously validate all iPSCs for pluripotency using immunofluorescence of stemness markers, RT-PCR, and SNP-based virtual karyotyping along with quality control methods established as a standard protocol. Results: We have a growing repository of &gt;1,000 iPSC lines with various disease backgrounds across demographics such as age, sex, race, and ethnicity. The diseases with genetic mutations include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), long QT syndrome (LQTS), arrhythmogenic right ventricular dysplasia / cardiomyopathy (ARVD/C), Brugada syndrome (BrS), Duchenne’s muscular dystrophy (DMD), Spinal muscular atrophy (SMA), and many other rare diseases and syndromes. We have also established a simple material transfer agreement (MTA) for open access by academic investigators. Conclusions: We introduce the Greenstone Biosciences iPSC Biobank, a biorepository containing &gt;1,000 human iPSC lines with de-identified patient clinical information and genetic backgrounds. This invaluable resource will help support iPSC research among academic investigators.
Abstract P3114: Sex Differences In Ventricular Function And Mortality In Sema3a Deficient Mice With Dilated Cardiomyopathy
Authors: MARISSA PENNINO, Alhassan Dajani, Jaime Contreras, Nigel M Arreola, Patrick Y Jay, Ching Zhu, Kalyanam Shivkumar, Olujimi A Ajijola
Journal: Circulation Research (2023)

Introduction: Clinical studies consistently report sex differences in heart failure (HF) outcomes. Disrupted cardiac sympathetic innervation patterns have not been investigated as a potential mechanism. Hypothesis: We aimed to explore whether cardiac sympathetic innervation patterns disrupted by deletion of the neurorepellent, Semaphorin3a (Sema3a), in murine dilated cardiomyopathy (DCM), has a deleterious effect in male compared to female mice. Methods: Utilizing the established Tg9 model of nonischemic HF (DCM+), we compared serial left ventricular ejection fraction (LVEF), ventricular arrhythmogenesis, mortality, and innervation patterns using immunohistochemistry in male vs. female DCM+Sema3a KO mice (with disrupted innervation) to male and female DCM+Sema3a WT animals. Results: Immunohistochemistry revealed greater disruption in sympathetic innervation amongst Sema3a deficient (DCM+Sema3a KO ) mice (n=11) compared to DCM+Sema3a WT (n=10) and WT mice (n=7) ( ****p&lt;0.0001). There was no significant difference in arrhythmogenesis between DCM+Sema3a WT versus DCM+Sema3a KO mice. Mortality was significantly greater in DCM+Sema3a KO mice compared to DCM+Sema3a WT and WT mice (*p=0.04). This was attributable to pump failure, as LVEF was lower in DCM+Sema3a KO mice that died compared to DCM+Sema3a KO mice who did not (*p=0.03). When outcomes were compared for male versus female mice, we observed sex differences in mortality, with female DCM+Sema3a KO mice exhibiting higher mortality and greater LV dysfunction than males (*p=0.03). This difference was not seen in male vs female DCM+Sema3a WT mice, suggesting that the sex differences are related to Sema3a gene deletion, and thus, disrupted innervation patterns, not DCM alone. Conclusion: Our data suggests that there are sex-based differences in DCM outcomes that may involve Sema3a signaling. Further studies validating this finding and identifying underlying mechanisms are warranted.
Abstract P1135: Gene Expression Analysis Of Glycemic Memory In Heart Failure
Authors: Sayan Bakshi, Adam R Wende
Journal: Circulation Research (2023)

Diabetes is a growing epidemic, with 37.3 million affected in the US. Diabetic patients are twice as likely to develop cardiovascular disease (CVD). Risk of CVD persists for years even following restoration of glycemic control in type-2-diabetic patients. These findings led to the hypothesis of glycemic memory, i.e., prior changes in glucose levels and delivery may lead to long-term molecular changes predisposing patients to CVD. We proposed that prior enhanced cellular glucose uptake leads to transcriptional changes that contribute to glycemic memory and enhances susceptibility to heart failure. We used a mouse model of doxycycline (DOX)-inducible cardiomyocyte-restricted glucose transporter 4 (GLUT4; mG4H), where mG4H is overexpressed for 2 wk (ON) and then returned to basal levels (OFF). Harvested left ventricular tissues from 4 groups of male mice (n=3) - ON and matched control (Con), OFF and DOX-matched Con (DCon) - were subjected to RNA sequencing analysis (Adjusted P &lt;0.1, Fold-Change&gt;
Abstract P1128: CRISPR-mediated Activation Of DLK1 Induces A Regenerative State In Engineered Human Myocardium
Authors: Branimir Berecic, Niklas Bader, Anastasia Rika, Eric Schoger, Eric Buchholz, Stephan von Haehling, Laura C Zelarayan, Christoph Dieterich, Karl Toischer, Wolfram H Zimmermann, Malte Tiburcy
Journal: Circulation Research (2023)

Background: The human heart displays limited potential to recover from injury. Delta-like non-canonical Notch ligand-1 ( DLK1 ) is an imprinted gene strongly expressed during embryo-fetal development. Expression in postnatal organs is low but re-expression commonly occurs in regenerative organs after injury. We hypothesized that enhancing DLK1 expression in engineered human myocardium (EHM) may induce a regenerative response. Methods and Results: RNA sequencing of muscle biopsies from non-failing (n=14) and failing (n=12) human hearts demonstrated a reduced expression of DLK1 in heart failure. In addition, serum levels of soluble DLK1 were reduced in patients with heart failure and correlated to left ventricular ejection fraction. Similar to patient samples, DLK1 expression was reduced in EHM with simulated heart failure. To test if DLK1 restoration prevents contractile dysfunction, we made use of a CRISPRa transgenic iPSC cell line, which stably expresses an enzymatic inactive dCas9 complex to specifically increase and modulate DLK1 expression. Cardiomyocyte-specific DLK1 activation ( DLK1 a) in EHM made with primary cardiac fibroblasts in a collagen hydrogel enhanced global DLK1 expression levels to 12±5 fold (n=5) of non-target (NT) control in simulated heart failure. While DLK1 a EHM showed comparable baseline function, contractile dysfunction by simulated heart failure was attenuated in DLK1 a EHM (Force of contraction: -13±5 % vs -45±5 % in DLK1 a vs NT EHM, n=8, p&lt;0.05). RNA sequencing identified a regenerative transcriptome pattern in DLK1 a EHM with differential expression of cell motility, extracellular matrix, cell cycle and metabolism-related processes. Conclusion: Reactivation of the developmental gene DLK1 induces a regenerative state and may protect from heart failure.
Abstract P1116: Histone Deacetylase Complexes Regulate Direct Cardiac Conversion From Human Fibroblasts
Authors: Meimei Wang, Yu-An Lu, Xinyue Zhou, Rui Lu, Yang Zhou
Journal: Circulation Research (2023)

Direct cardiac reprogramming is a promising approach to generate functional cardiomyocytes from non-myocytes for regenerative medicine, drug screening, and disease modeling. This method involves the transformation of specialized cells into functional cardiomyocytes using specific transcription factors or molecular signals. Epigenetic modulators, such as histone deacetylase (HDAC) complexes, may play a critical role in chromatin remodeling underlying cardiac reprogramming. To investigate the role of HDAC complexes in direct cardiac conversion, induced cardiomyocyte-like cells (iCMs) were derived from human fibroblasts through ectopic expression of reprogramming factors, and the changes of histone acetylation were evaluated by western blotting. The results showed decreased levels of H3K9ac, H3K14ac, and H3K27ac along with direct cardiac reprogramming, suggesting the significant chromatin remodeling and gene regulation. A loss-of-function screen of all the components associated with HDAC complex was performed to determine the responsible histone acetylation modifiers. The screen results showed that most of the HDAC components are necessary for direct cardiac reprogramming. Further investigation focused on a newly identified HDAC complex, mitotic deacetylase complex (MiDAC), consisting of mitotic deacetylase associated SANT domain protein MiDEAS (ELMSAN1), DNTTIP1, and HDAC1. Knocking down each of the MiDAC components led to similar reprogramming repression and cell death, indicating that MiDAC plays a critical role in cardiac reprogramming. In addition, the expression analysis of DNTTIP1 and HDAC1 showed a gradual decrease throughout the conversion, while ELMSAN1 diminished at the early stage of reprogramming, suggesting that ELMSAN1 is likely required for MiDAC stability. Furthermore, overexpression of ELMSAN1 significantly improved reprogramming efficiency and led to the increase of H3K9ac, H3K14ac, and H3K27ac levels globally, suggesting that ELMSAN1 and MiDAC might be responsible for the regulation of such histone modifications during the process. Overall, our findings provide novel insights into the epigenetic regulation of direct cardiac reprogramming and reveal the potential role of MiDAC in this process.
Abstract P1159: Association Of Membrane Ferritin Transporter And Transferrin Receptor Plasma Levels With Coronary Atherosclerosis
Authors: Jia Li, Rayaan Yunus, Faraz Mahmood, Yifan Bu, Dan Song, Robina Matyal, Hebin Xie, Yiping Leng, Ping Deng, Qiaoqing Zhong
Journal: Circulation Research (2023)

Objective: Given the potential role of iron in inflammation and atherosclerosis, we investigated the correlation between the plasma levels of membrane ferritin transporter (FPN) and soluble transferrin receptor (sTFR) with the severity of coronary artery stenosis (CAS). Methods: Clinical data of 85 patients admitted to our institution between August 2022 and December 2022 with suspected coronary artery disease (CAD) was utilized. Patients were stratified according to their coronary angiography results: CAD group (n=50) and control group (n=50). Patients with CAD were further divided depending on their use of statin: statin taking group (PSU, n=15) and non-statin taking group (NSU, n=35). The coronary Gensini score was used to assess the severity of CAS. Spearman’s regression analysis was used to correlate plasma FPN and sTFR concentrations with the severity of CAS. Results: Plasma sTFR [2,216.88 (1,922.42, 2479.01) ng/mL vs. 1,928.96 (1490.50, 2289.23) ng/mL] concentration was higher in patients with CAD, while HDL cholesterol [0.94 (0.84, 1.17) mmol/L vs. 1.14 (0.95, 1.38) mmol/L] and plasma FPN [0.71 (0.42, 2.71) ng/mL vs. 2.90 (1.32, 4.40) ng/mL] concentration was lower when compared to patients without CAD. The coronary Gensini score was positively correlated with plasma sTFR concentration (R s =0.24, p =0.045) and negatively correlated with plasma FPN concentration (R s =-0.28, p =0.021). Plasma FPN level [1.50 (0.52, 4.77) ng/mL VS 0.51 (0.28, 2.46) ng/mL, P=0.007] in PSU patients was higher than the NSU group. Levels of total cholesterol [3.71±0.28mmol/L VS 4.67±0.15mmol/L, P=0.002] and low-density lipoprotein [2.24±0.25mmol/L VS 2.96±0.10mmol/L, P=0.002] were significantly lower in the PSU group. Regression analysis indicates that low plasma FPN concentration is an independent risk factor for the development of CAD ( p =0.038). Conclusion: Our results suggest that sTFR and FPN concentrations are positively and negatively correlated respectively with the severity of CAS. Furthermore, regression analysis indicates that low plasma FPN concentration is an independent risk factor for the development of CAD. While our data provides some reference for evaluating the incidence and severity of CAD, future research is needed to verify our results.
Abstract P2007: Novel Regulatory Axis In Heart-adrenal Cross Talk Mediated By Mtor-eprs
Authors: Tian Liu, Ye Zhang, Junyi Yu, Shuxun Ren, Cansheng Zhu, Christoph D Rau, Yibin Wang, Chen Gao
Journal: Circulation Research (2023)

Adrenal catecholamines, including norepinephrine and epinephrine play an important role in cardiovascular physiology. Serum catecholamine level is tightly regulated in response to metabolic and cardiac stress. The biosynthesis of catecholamine is driven by a series of enzymatic reaction carried out by the key rate-limiting enzymes, including tyrosine hydroxylase (TH), DOPA decarboxylase (DDC) and phenylethanolamine-N-methyltransferase (PNMT). Although the transcription regulation of these enzymes has been described before, the regulatory mechanism at post-transcription or protein translation level has never been explored. Using a system genetics approach, we explored genes associated with the adrenal gland traits in HMDP at basal and post isoproterenol treatment. We have identified EPRS (Glutamyl-Prolyl-tRNA synthetase) to be significantly associated with adrenal gland mass post ISO treatment. EPRS is a tRNA synthetase responsible for charging tRNA during protein translation, EPRS also regulates mRNA translation as an RNA binding protein. To explore the functional impact of EPRS in adrenal gland physiology, we generated an EPRS adrenal gland specific knockout mouse model (EPRS-aKO). Inactivation of EPRS in adrenal gland led to a decrease of adrenal gland mass associated with reduced systemic catecholamine level. Interestingly, we further observed a moderate yet significantly decreased heart rate and ejection fraction in EPRS-aKO mice. Through both in vivo and in vitro analysis, we confirmed inactivation of EPRS led to a reduced protein, but not mRNA expression for both TH and DDC. In adipose tissue, activation of EPRS through mTOR signaling pathway is critical for its function as RNA binding protein. To further explore the mechanism through EPRS mediated catecholamine synthesis, we treated PC12 cells with rapamycin to inhibit mTOR activity. Treatment with Rapamycin diminished EPRS activity and expression, reduced TH protein expression along with a decrease of catecholamine level. Our results identified a novel regulatory scheme of catecholamine synthesis through mTOR-EPRS axis, adding a novel layer of gene regulation in catecholamine production and providing new mechanistic insights for heart-adrenal cross talk.
Abstract P1139: Remodeling Chromatin Structure To Induce And Reverse Heart Failure
Authors: Manuel Rosa-Garrido, Justin Bridges, Douglas Chapski
Journal: Circulation Research (2023)

Heart failure is a critical health issue that causes one in nine deaths in the United States. Despite extensive research on gene expression dynamics in the failing myocardium, the mechanisms by which the genome reorganizes itself to reconfigure transcription are poorly understood. CTCF is a crucial protein in chromatin architecture that mediates chromatin looping, acts as an enhancer insulator, and can function as either an activator or repressor of transcription. Our previous research indicates that CTCF plays a crucial role in heart failure, as cardiac-specific knockout of this protein promotes genome organization defects that result in cardiac pathology marked by reduced ejection fraction. To determine whether restoring CTCF levels could reverse this phenotype, we designed an AAV9 vector in which the cardiomyocyte-specific Troponin T promoter drives the expression of CTCF and GFP. Our results show that reintroduction of CTCF into failing CTCF-depleted mouse hearts successfully rescues the pathological phenotype of the animals, characterized by sustained improvement in ejection fraction and left ventricular chamber size in both systole and diastole. Furthermore, RNA-seq experiments reveal numerous differentially expressed genes with opposite transcriptional behavior depending on CTCF levels, including genes involved in chromatin organization (e.g., CHmgb2, Brca1, Smyd2), development of hypertrophy (e.g., Mef2a, Gata4, Mybpc3), extracellular matrix organization (e.g., Adamts5, Itgb1, Vtn) and collagen deposition (e.g., Col5a1, Col5a3). We also examined chromatin architecture through Hi-C experiments and discovered that restoration of CTCF levels remodels the global architecture of chromatin to closely resemble healthy myocyte chromatin. This finding supports the hypothesis that rescue of CTCF levels ameliorates cardiac disease by reverting the observed pathological gene expression profile through genomic reorganization. In summary, our project highlights the crucial role of CTCF in heart failure and demonstrates that structural repair of chromatin organization through modulation of CTCF levels is a novel and realistic approach to treating heart failure.
Abstract P2145: A Review Of Trends In Cardiovascular Medicine Clinical Trials; 2012-2021
Authors: Bharat Rawlley, Kannu Bansal, Utkarsh Dayal, Dhawani Julka, Ishita Salooja, Andres Cordova Sanchez, Sandeep Kumar, Debanik Chaudhuri
Journal: Circulation Research (2023)

Introduction: We examine cardiovascular medicine clinical trials (CTs) from the United States over the past decade focusing on characteristics that are important for assessing the reliability of evidence derived from them. Methods: The Clinicaltrials.gov API interface was queried with a comprehensive search strategy to identify trials in the field of cardiovascular medicine from the US registered from 1/1/2012 till the 12/31/2021. We extracted data on the presence of data monitoring committees (DMC), masking status and allocation methods used in the CTs. Results: Our initial query identified 1299 CTs. After reviewing and excluding unrelated trials, 536 were found to be cardiovascular medicine CTs. Of these, 507 (95%) reported if they had a DMC or not, 261 (49%) reported having a DMC while 246 (46%) reported not having one. 471 (88%) CTs reported on their design allocation method, most common being randomized as reported by 312 (58%) of the trials, 43 (8%) were non-randomized and 116 (22%) reported that a design allocation was not applicable to them. 471 (88%) CTs reported on their masking status, most common being open label as seen in 247 (46%) of the trials followed by double masking seen in 71 (13%) of the trials. On performing a Cox and Stuart trend test, no trend was seen in the annual proportion of trials with randomization, a DMC or masking over the past decade [P &gt; 0.05 for all three]. Conclusions: In these analyses of 536 CTs, we found that &gt; 50% did not have a DMC or any masking and no favorable trend was seen in the annual proportion of same over the past decade. Additionally, majority of the trials reported randomization as the design allocation method.
Abstract P2182: Cardioprotective Effect Of APE1/Ref-1 In Doxorubicin-induced Cardiotoxicity
Authors: Soo Yeon An, Hee Jeong Seo, Seon-Ah Jin, Jin-Ok Jeong
Journal: Circulation Research (2023)

Doxorubicin is a potent anthracycline anticancer drug widely used to treat various malignancies. Unfortunately, it can cause negative side effects such as cardiomyopathy. Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a versatile protein capable of being secreted from cells, but the role of secreted APE1/Ref-1 in doxorubicin-induced cardiomyopathy remains unknown. In this study, we used Adenoviral preprotrypsin leading sequence APE1/Ref-1 (Ad-PPTLS-APE1/Ref-1) to overexpress secreted APE1/Ref-1 in cells and mice through transfection. We aimed to investigate the potential role of secreted APE1/Ref-1 in preventing doxorubicin-induced cardiomyopathy, a serious side effect associated with the use of this widely used anticancer drug. Our findings reveal that exposure to secreted APE1/Ref-1 significantly decreases NT-proBNP levels, a known marker for cardiomyocyte injury, in doxorubicin-treated H9C2 cells. Furthermore, secreted APE1/Ref-1 was found to reduce the severity of cardiomyocyte injury and apoptosis both in vitro and in vivo models of doxorubicin cardiotoxicity. These cardioprotective effects were mediated through the inhibition of the p53 signaling pathway and the enhancement of cell viability in doxorubicin-treated cardiomyocytes.Our study provides evidence that secreted APE1/Ref-1 has the potential to attenuate oxidative stress and inhibit doxorubicin-induced apoptosis both in vitro and in vivo. Based on our results, supplementing secreted APE1/Ref-1 to patients at high risk of doxorubicin-induced cardiotoxicity could be a promising strategy for reducing the harmful effects of doxorubicin. Further studies are needed to fully understand the mechanism by which APE1/Ref-1 protects against doxorubicin-induced cardiotoxicity and to determine if this finding can be translated to human patients.
Abstract P2002: Variability In The Relationship Between Heart Rate And Automatic Breathing Rate Throughout The Mouse Lifespan
Authors: Suri Gime, Ismayil Ahmet, Christopher Morrell, Edward G Lakatta
Journal: Circulation Research (2023)

Background: Autonomic neural surveillance maintains a symphonic relationship between heart and breathing rhythms. We have established how heart beat interval variability changes across mouse lifespan (6 months - 30 months) in the presence and absence of double autonomic blockade (Baltimore Longitudinal Study on Aging in Mice, BLSAM; Geroscience 2022, PMID: 35759167). Objective: To determine how the automatic breathing rate (BR) changes with age in the same BLSAM cohort, and whether the BR and Heart Rate (HR) track each other in the presence and absence of double autonomic blockade across the lifespan of individual mice. Methods: The BLSAM cohort consists of 58 mice in which HR and BR were assessed from the EKG (under light anesthesia) at 3-month intervals, beginning at 6 months of age until the end of life (30 months of age). EKG was recorded in the presence and absence double autonomic blockade (i.p injection of atropine, 0.5mg/kg, and propranolol, 1mg/kg). Data were analyzed via a mixed ANOVA. Results: The BR remained stable until approximately 21 months of age, and then became sharply reduced between 21 and 30 months of age (Fig. A). The pattern of HR change over the adult life span was similar to that of BR (Fig. B). Both HR and BR were significantly (p&lt;0.05) reduced in the presence of double autonomic blockade (arrows in figs). The relative magnitude of BR reduction beyond 21 months of age was substantially greater than the relative reduction in HR over this age range, resulting in a marked increase in HR/BR Ratio (Fig. C), which was also significantly impacted by autonomic function. Conclusion: Thus, beginning at approximately the 70% of maximum mice lifespan, the harmony between heart rhythm and breathing rhythm gradually deteriorates.